tbuckley/cabot-search huggingface dataset:
Comparison of synchronous neoplasms at colonoscopic diagnosis of early-onset versus average-onset colorectal cancer.
Authors: Oluwadunni Eunice Emiloju, Bahar Saberzadeh Ardestani, Frank A. Sinicrope
Journal: Journal of Clinical Oncology (2023)

3623 Background: Colorectal cancer (CRC) incidence has steadily increased in adults younger than 50 years (EO-CRC) since the 1990s, with a predominance in the left colon and rectum. Precursor lesions of CRCs are adenomas, including advanced adenomas, and sessile serrated polyps. Given that neoplastic development is age-related, we hypothesized that patients with early-onset CRC (EO-CRC) may have fewer adenomas compared to patients with average-onset CRC (AO-CRC) at diagnosis. Methods: We performed a retrospective review of electronic health records at Mayo Clinic or Mayo Health System [2012 to 2021] and randomly selected 150 patients with EO-CRC who met eligibility criteria and matched them with 150 AO-CRC patients based on gender and colonoscopy indication. Known hereditary syndromes or inflammatory bowel disease were excluded. At colonoscopy where CRC was diagnosed, we recorded findings of adenomas, advanced adenomas (&gt; 1 cm, villous histology, or high-grade dysplasia), and sessile serrated polyps (SSP). Results: Median age at diagnosis was 43 years for EO-CRC and 67 years for AO-CRC. No significant differences in BMI, family history of CRC, MMR, BRAF V 600E KRAS status or SSPs were found between groups (all p &gt; 0.05). Among patients with colon cancer, no difference was found for adenoma number yet patients with EO-colon cancer (EO-CC) had larger polyps [median of 10 mm vs 5 mm, p = 0.001] (Table) compared with AO-colon cancer (AO-CC). At least 1 adenoma was found in 56% and 47% of patients with EO-CC and AO-CC, respectively. Moreover, advanced adenomas were significantly more common in the EO-CC group compared with the AO-CC group (42% and 14%, p &lt; 0.001) [ Table]. Among patients with rectal cancer, non-advanced adenomas were less frequent and although advanced adenoma were similar in frequency, they were more commonly located in the rectum in EO-rectal compared to AO-rectal cancers (Table). Conclusions: Patients with EO-colon cancer had a significantly higher likelihood of a synchronous advanced adenoma in the colon compared to those with AO-CRC. Together, these data suggest accelerated carcinogenesis throughout the colorectum in early onset patients, with increased risk for development of synchronous and metachronous CRC. [Table: see text]
Use of proteomimetic polymers for delivery of tumor antigens and adjuvants through formation of stable electrostatic complexes with small molecule STING agonists.
Authors: Max Mu Wang, Brayley Gattis, Mi Ran Choi, Bin Zhang, Nathan Gianneschi
Journal: Journal of Clinical Oncology (2023)

2583 Background: Utilizing tumor antigens for the development of patient-specific cancer vaccines has been a promising therapeutic strategy. However, significant challenges remain in delivering subunit vaccine components to elicit antitumor immune responses. To overcome these, we developed rationally designed cancer vaccines using a new nanoplatform called the Protein-Like Polymer (PLP) with unique characteristics that allow for sustained delivery of tumor antigens in conjunction with immunomodulatory compounds. Methods: PLPs containing antigens were synthesized via ring-opening metathesis polymerization (ROMP) and characterized using HPLC, LC-MS, NMR, and GPC. A library of compounds were generated with different sidechain linkage chemistries (amide, ester, or disulfide linkage), DPs, and inclusion of PEG side chains. In vitro assays using gp100-specific T Cells were conducted with fluorescently labeled and non-labeled polymers. In vivo experiments were done using B16 murine melanoma transplanted tumor models. Ability of PLPs to co-deliver immunomodulatory compounds was tested using a small molecule STING agonist 2’3’ cGAMP. Results: Conjugating antigens to the polymer backbone using a cleavable disulfide linkage, designed to be reduced intracellularly, resulted in the best subcellular localization and immune activation (higher levels of immune cell proliferation, cytokine production, and expression of activation markers). Incorporating a diluent amount of PEG side chains increased resistance to enzymatic degradation while improving bioactivity and cell uptake. In vivo studies using PLPs conjugated with melanoma-associated antigen gp100 showed the reductions in tumor size with increased immune cell proliferation and activation in a B16 melanoma model. Additionally, increasing the degree of polymerization, and therefore the density of antigen side chains per unit polymer, improved vaccine efficacy and resistance to proteolysis. Mice treated with STING agonists electrostatically coupled to PLPs showed significantly smaller tumors vs no-treatment at day 14 (0.038g vs 0.76g; p &lt;0.0001) and allowed for subcutaneous administration of the small molecule, which normally must be injected intratumorally. Conclusions: Our work demonstrates the potential of PLPs to overcome inherent difficulties associated with developing cancer vaccines. The modularity of the platform allows for complex nano-architectures including systems capable of delivering challenging compounds, ie small molecule STING agonists, subcutaneously through electrostatic coupling. This technology has the potential to revolutionize cancer vaccinology.
Immunotherapy in locally advanced and metastatic rectal cancer: A propensity score matched analysis of the National Cancer Database.
Authors: Nir Horesh, Sameh Hany Emile, Michael Freund, Zoe Garoufalia, Rachel Gefen, Peige Zhou, Arun Nagarajan, Steven D Wexner
Journal: Journal of Clinical Oncology (2023)

e15633 Background: Immunotherapy has been increasingly used in cancer therapy. In rectal cancer, patients with high microsatellite instability (H-MSI) are candidates for immunotherapy, but there is little evidence on its effect on overall survival. Methods: A retrospective analysis of all patients with stage II-IV rectal adenocarcinoma in the US National Cancer Database (NCDB) between 2010 and 2019 was performed. Patients without data on whether or not they had immunotherapy were excluded. Propensity-score matching was used to adjust for baseline and treatment confounders and the cohort was divided into two groups: patients who received immunotherapy and matched controls. The primary outcome was overall survival. Secondary outcomes included 30-day readmission and 30- and 90-day postoperative mortality. Results: 5175/206,615 (2.5%) patients with rectal adenocarcinoma were treated with immunotherapy during the study period. Patients treated with immunotherapy were younger (58 vs 62 years; p &lt; 0.001), more often male (64.4% vs 61.7%; p &lt; 0.001) and had more private insurance (50.8% vs 43.4; p &lt; 0.001) compared to controls. Patients treated with immunotherapy had more metastatic disease at presentation (clinical TNM Stage IV - 80.8% vs 23.3%; p &lt; 0.001), presented with larger tumors (median: 5 vs. 4.2 cm; p &lt; 0.001) and less often underwent surgery (33.7% vs. 69.9%; p &lt; 0.001), radiation therapy (21.5% vs 57.4%; p &lt; 0.001) and standard chemotherapy (38.1% vs 61%; p &lt; 0.001). After matching, 488 patients were included in each group. Overall survival was significantly shorter in the immunotherapy group, with a mean survival of 56.4 months (95%CI – 53.03-59.86) compared to 70.5 months (95%CI – 66.15-74.92) in the control group (p = 0.004). Cox regression analysis of factors associated with overall survival demonstrated that, for the entire cohort, immunotherapy was associated with an increased mortality (HR 2.16; 95%CI: 2.09-2.24; p &lt; 0.001). After stratifying based on clinical staging, immunotherapy was associated with improved overall survival in stage IV patients (HR 0.91, 95%CI 0.88-0.95; p &lt; 0.001) but with lower survival in stage II (HR 2.38; 95%CI: 2.05-2.77; p &lt; 0.001) and stage III (HR 2.43; 95%CI: 2.18-2.7; p &lt; 0.001). Conclusions: Immunotherapy was associated with a modest increase in overall survival in patients with stage IV metastatic rectal cancer. However, overall survival was significantly lower in patients with Stage II-III disease when treated with immunotherapy.
Safety and clinical efficacy of sintilimab in pediatric patients with advanced or recurrent malignancies in a phase I study.
Authors: Yi Que, Suying Lu, Juan Wang, Feifei Sun, Jia Zhu, Junting Huang, Zijun Zhen, Yizhuo Zhang
Journal: Journal of Clinical Oncology (2023)

e14601 Background: This is a first phase I study investigating the safety and efficacy of sintilimab in pediatric patients with advanced or recurrent malignancies. Methods: During dose escalation, patients received a single-dose intravenous infusion of sintilimab. The planned dosing groups were 1, 3 and 10 mg/kg. During dose expansion, patients received sintilimab every three weeks. Primary endpoints were determination of dose-limiting toxicities at the maximum administered dose, safety and tolerability, and the proportion of patients with objective response to sintilimab according to the Response Evaluation Criteria in Solid Tumours version 1.1. PD-L1 expression of tumor in subjects were identified by immunohistochemistry (DACO,22C3). Whole exome sequencing (WES) was performed in 15 patients to characterize the mutational landscape and CNV status. Results: 29 patients were enrolled, including 10 patients with Hodgkin lymphoma (HL), 19 patients with other tumor types. Some special pathological types, including thymoma, choroid plexus carcinoma, and NK-T cell lymphoma are included. Patients were pretreated with a median of 3 prior lines of systemic treatment. Sintilimab was well tolerated without dose-limiting toxicity. By the safety data cutoff date, all patients experienced treatment related adverse events (TRAE) with most adverse events being grade 1 or 2, and ≥ grade 3 TRAEs occurred in 10%. Among all 27 subjects evaluated, 4 confirmed complete response (2HL, 1 NK/T lymphoma, 1 anaplastic ependymoma), 7 confirmed partial responses (4 HL, 1 Ewing sarcoma, 1 diffuse large-B lymphoma and 1 thymoma), and 7 stable disease were observed, for an objective response rate of 40.7%, and a disease control rate of 66.7%. Subjects with PD-L1-positive expression benefited more from sintilimab treatment than PD-L1-negative subjects (66.7% ORR versus 33.3% ORR, p=0.314) although statistically insignificant. The genomic profiling of WES indicatedpatients with a specific genomic mutation type predict the response of PD-1 therapy. Conclusions: Sintilimab was well tolerated and demonstrated promising anti-tumor activity in pediatric HL. The completion of the current phase I study has led to the initiation of the first prospective anti-PD-1 registration trial in Asia focusing on pediatric patients and serve as the basis for its potential study in combinatorial regimens for childhood cancer. Clinical trial information: NCT04400851 . [Table: see text]
Pharmacokinetics (PK) of epacadostat in combination with sirolimus in advanced malignancy.
Authors: Chao Hui Huang, Takefumi Komiya, Anup Kasi, Stephen K. Williamson, Scott James Weir, Joaquina Celebre Baranda
Journal: Journal of Clinical Oncology (2023)

e14589 Background: Epacadostat (E) is an inhibitor of Indoleamine 2,3 dioxygenase-1 (IDO1) which is a rate-limiting enzyme in the catabolism of tryptophan to kynurenine. The inhibition of IDO1 leads to increase tryptophan and reversal of immunosuppression by increasing the proliferation of T cells, suppression of regulatory T cells (Tregs) and activation of mTOR which suppresses autophagy. Sirolimus (S) can reverse the mTOR activation induced by E, suppress the expression of PD-L1 and function of Tregs. We initiated a phase I trial to test the safety and tolerability of SE combination in patients (pts) with advanced solid tumors and performed PK studies. Methods: The phase I trial portion of the study used a modified 3+3 design in which the dose transition rule was similar to standard 3+3 design with the modification based on sirolimus PK data. S had a lead-in of 3mg/day(d) at d -7 followed by 1mg/d with E added on d1 of Cycle(C) 1 starting at 100mg bid in a 28d C at dose level 1; then S is escalated to 6mg/d followed by 2mg/d maintenance with E at 300mg bid at level 2. An additional level 3 was added with S at 6mg/d followed by 2mg/day with E at 400mg bid based on results of E at 400-600 mg bid in combination with a checkpoint inhibitor with improved control of peripheral kynurenine and intra-tumoral kynurenine reductions. PK samples from plasma samples for determination of plasma E concentrations were obtained on C1d1, prior to administration of the first E dose. Plasma samples were also obtained on C1d1 at two hours post-dose, coinciding with the previously reported Tmax for E. For pts continuing E treatment, plasma samples were obtained on C2d1, prior to dosing (representing trough drug concentrations) as well as at two hours (representing Cssmax). Results: The phase I study enrolled 15 pts. The types of cancers were non-small cell lung ca (1), colorectal (5), esophagus (1), gallbladder (1) and sarcoma (1). Mean values as well as the range of plasma E concentrations observed in the three dose cohorts at each collection time are summarized. Conclusions: The combination of SE showed results consistent with reports that E accumulates upon repeat administration in a dose-proportional fashion. Plasma concentrations of E observed across the three dose cohorts are also consistent with those previously reported. Due the small number of pts studied, and moderate variability in PK reported for this drug, it is not possible to draw definitive conclusions regarding dose-proportionality. Mean (range) plasma E concentrations (ng/mL) determined in samples obtained from pts at trough and two hours post-dose during treatment C1 and C2. Clinical trial information: NCT03217669 . [Table: see text]
Clinical outcomes and genomic landscape of patients (pts) with EGFR-mutant lung cancer (EGFR+ LC) with central nervous system (CNS) metastases (mets).
Authors: Jane Sze Yin Sui, Jessica Wilcox, Samuel Tischfield, Noura J. Choudhury, Gregory J. Riely, Mark G. Kris, Adrienne Ann Boire, Helena Alexandra Yu
Journal: Journal of Clinical Oncology (2023)

e21146 Background: CNS mets are a major cause of morbidity and mortality in pts with LC. Up to 50% of pts with EGFR+ LC develop CNS mets over their disease course despite improvements in anti-EGFR therapies. The genomics alterations present in CNS mets in pts with EGFR+ LC and how these may compare to paired systemic samples has not been reported. Furthermore, it is unknown whether there are baseline clinicogenomic features that differ between EGFR+ LC pts with or without (w/wo) CNS mets. Methods: From an institutional database of LC pts with available next-generation sequencing (NGS) completed by MSK-IMPACT, we identified all EGFR+ LCs with molecularly characterized CNS tumor samples (CTS). We subsequently identified all pts with EGFR+ LCs with available paired CTS and systemic tumor samples (STS) profiled with MSK-IMPACT. All pts treated with 1L osimertinib with MSK-IMPACT available on their STS were also identified. We assessed clinicogenomic features of all selected EGFR+ LCs. Comparisons of frequencies of genes altered by somatic alterations were performed using Fisher’s exact test and logistic regression. Results: From 2014 to 2022, 90 EGFR+ LC pts with NGS performed on CTS were identified [brain metastasis (BrM), n = 38; leptomeningeal w/wo BrM (LM), n = 52]. 69 pts (77%) were female, median age 59 (IQR range:53-66 years), and 51 pts (57%) were never smokers. Patterns of EGFR+ were exon 19del (n = 43), L858R (n = 27) and atypical (n = 20). No genomic mutations were differentially altered in pts with LM vs BrM. Paired CTS and STS were available for 28 pts, where numerically higher rates of CDKN2A, CDKN2B loss and RAC1 amplification were seen in the CTS (respectively 43% vs 18%, 43% vs 18%, and 21% vs 0%, q &gt; 0.05 for all). A total of 263 pts on 1L osi had NGS on their STS performed:136 pts (52%) had CNS mets during their disease course to date [94 pts (69%) de novo CNS mets; 42 pts with on-treatment CNS mets with median time to CNS mets of 25 mo (IQR: 13.5-35.3 mo)]. Between pts w/wo a lifetime history of CNS mets, there were no differences in sex, smoking history, EGFR alterations and co-alterations. CARD11 alterations were numerically higher in STS in pts with CNS mets (12% vs 2%, q &gt; 0.05). Conclusions: In patients with EGFR+ LC, there were no genomic alterations that were significantly enriched in CNS mets compared to systemic disease, and no systemic genomic alterations that differentiate pts w/wo CNS mets.
A phase I/IIa study to assess the safety, tolerability, PK, and PD of T3011, a genetically modified oncolytic virus (OVs) administered intravenously (IV) in patients with advanced solid tumors.
Authors: Ziming Li, Jian Zhang, Shuang Zhang, Li Zheng, Zhiye Zhang, Junbin Wang, Ying Hu, Su-xia Luo, Weijia Pang, Wenmin Fu, Yanmei Qin, Shun Lu
Journal: Journal of Clinical Oncology (2023)

2640 Background: T3011 is a genetically modified, next-generation oncolytic HSV-1 with 2 exogenous genes encoding the active heterodimer human IL-12 and the Fab fragment of an anti-human PD-1 antibody. T3011 intratumoral injection (IT) was reported to be well tolerated in patients (pts). IV therapy of OVs is rare and provides an attractive option to many pts with advanced cancers that are not candidates for IT therapy. Methods: It is a phase I/IIa multi-center, open label, single ascending dose (SAD) /multiple ascending dose (MAD) study to evaluate T3011 IV therapy. The primary objective is to evaluate the safety and tolerability. Dose cohort and regimen are shown in Table. PK and PD profiles are tested in samples of blood, saliva, urine, and tumor tissue. Results: As of 16 Dec 2022, 15 pts with stage IV disease were enrolled, 9 pts had received at least 3 lines of prior therapy. The median follow-up time is 1.58 months. Treatment-emergent adverse event (TEAE) occurred in 15 (100%) pts and treatment-related adverse event (TRAE) occurred in 10 (66.7%) pts. G3 TEAE in 3 (20%) pts (hypertriglyceridemia, dyspnea, lymphopenia) and G3 TRAE in 1 (6.7%) pt (lymphopenia), no≥ G4 AE reported. Dyspnea, the only reported SAE (1, 6.7%), is drug-unrelated. TRAEs were lymphopenia (5, 33.3%), anemia (1, 6.7%), diarrhea (1, 6.7%), malaise (1, 6.7%), urticaria (1,6.7%), rash (1, 6.7%), constipation (1, 6.7%), flu like symptoms (1, 6.7%), headache (1, 6.7%) and abnormal laboratory test results (incidence were all 6.7%), most of them are mild and manageable. No AEs led to drug withdrawal. No DLT occurred; MTD was not reached. 11/15 pts achieved stable disease (SD) by RECIST v 1.1. DCR was 73.3%. 1 pt with colorectal cancer who experienced irinotecan-based chemotherapy, anti-VEGF and radiotherapy in Cohort 1 had a long-term SD for over 4 months. In SAD part, T3011 DNA in blood at 2 hours post-dose was detected in 0% (0/3), 0% (0/4), 66.7% (2/3) and 100% (2/2) pts in Cohort 1, 2, 3 and 4 respectively. The DNA copies in pts of Cohort 4 are significantly higher than those of Cohort 3 (Mean viral DNA copies/ul 49.6 vs. 5.7). In cohort 2 of MAD part, T3011 DNA in blood at 2 hours post-dose was detected in 0% (0/3), 66.7% (2/3) and 100% (3/3) pts at C1D1, C1D4 and C1D8 respectively. T3011 DNA was not detected in saliva or urine samples. Pre-existing HSV-1 IgG was shown to hardly affect T3011 activity. Conclusions: T3011 IV is safe and well tolerated, and unlikely to spread to close contacts. Preliminary efficacy is encouraging. T3011 DNA in blood is in a dose-dependent manner with additive effect from repeated doses supporting continued recruitment of pts to higher dose cohorts. Clinical trial information: NCT05598268 . [Table: see text]
A phase I study of nelmastobart (hSTC810), an anti-BTN1A1 antibody, in patients with advanced solid tumors.
Authors: Soohyeon Lee, Sangjoon Shin, Patricia LoRusso, Christian Diego Rolfo, Hyunjin Jung, Stephen Sunghan Yoo, David S. Hong
Journal: Journal of Clinical Oncology (2023)

2633 Background: Butyrophilin 1A1 (BTN1A1) is a novel immune checkpoint that is primarily expressed by tumor cells in a manner that is mutually exclusive with PD-(L)1. BTN1A1 can potentially be targeted to extend new immunotherapeutic treatment options to patients (pts) whose tumors are unresponsive to anti-PD-(L)1 therapy. This phase I study describes the safety and clinical activity of Nelmastobart (hSTC810), a humanized monoclonal antibody targeting BTN1A1, in pts with advanced solid tumors. Methods: Nelmastobart was administered intravenously every 2 weeks across 6 dose levels from 0.3 mg/kg to 15 mg/kg. The primary objectives were to determine the safety profile and maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D). Using a 3+3 design, dose-escalation cohorts were evaluated for dose-limiting toxicities (DLT) during the first 2 cycles. Backfill cohorts were allowed once a dose was deemed safe. Response was assessed using RECIST 1.1 every 4 cycles (8 weeks). Pts were treated until disease progression or unacceptable toxicity. Results: As of January 30, 2023, enrollment in the dose-escalation cohorts is complete. A total of 39 pts with colon (n=14), lung (NSCLC n=3; SCLC n=2), urothelial (n=3), breast, cholangiocarcinoma, melanoma, ovarian, pancreatic (n=2) each, adrenocortical, anal, esophageal, H&amp;N, PEComa, skin, and thymic (n=1) cancers each were treated in the dose-escalation and backfill cohorts. Median duration of therapy for all pts was 8 weeks (maximum 29 weeks). Most common treatment related adverse events (TRAEs) reported were grade 1-2 fatigue (6%), headache (5.9%), and nausea (4.4%); furthermore, there were no TRAEs ≥ 3. No pts was discontinued or required dose reduction due to TRAEs. There were no DLTs across all dose levels and the MTD was not reached. In evaluable pts, one confirmed partial response was observed in MSI-H colon cancer (3 mg/kg) and 13 pts (colon, H&amp;N, lung, melanoma, ovarian, thymic carcinoma) had a best response of stable disease (SD) across multiple dose levels. Median duration of PR/SD pts on study was 17.5 weeks. Interim pharmacokinetics (PK) analysis demonstrated consistent exposure with linear PK. Pharmacodynamic analysis measuring cytokines and cell-based markers is pending and will be presented. Based on the safety, efficacy, and PK, we recommend 15 mg/kg Q2W as the RP2D. Conclusions: Nelmastobart is well-tolerated without DLTs up to the final dose of 15 mg/kg. Current data show evidence of anti-tumor activity and durable SD. Clinical development planning for a phase Ib/II clinical trial is underway to further characterize the therapeutic dose and efficacy in select solid tumors. Clinical trial information: NCT05231746 .